Liver Transplant
Conditions
Keywords
De Novo Liver Transplant, Tacrolimus Minimisation, Everolimus, Renal Function, Liver transplant, allograft rejection, xenograft rejection, host vs graft disease
Brief summary
Assuming greater efficacy in the prevention of acute rejection in the EVR arm with minimisation of TAC levels, the hypothesis of the present trial was that the introduction of EVR in combination with the minimisation of TAC (rTAC) may offer improved kidney function compared with standard therapy with TAC-MMF.
Detailed description
A multicentre, randomized, open-label, controlled, exploratory clinical trial with 12-months (52 weeks) of follow-up.
Interventions
DRUGMinimisation of TAC
•EVR: Treatment started at a total daily dose of 2 mg within 24 hours after randomisation. The dose of EVR was adjusted upon reaching trough levels (C-0h) in whole blood of 3-8 ng/mL. The daily dose (in two administrations) of EVR may have been modified to maintain trough levels (C-0h) in whole blood of 3-8 ng/mL until Week 52 post-transplant. •TAC: Once confirmation was obtained, beginning in Week 5, that trough levels (C-0h) in whole blood of EVR were between 3-8 ng/mL, minimisation of TAC began, in order to reach trough levels (C-0h) of TAC in whole blood of ≤5 ng/mL no later than four weeks after randomisation (Week 8), which were levels that should have been maintained until Week 52 post-transplant. •MMF was withdrawn at the same time that EVR was introduced. •oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted
DRUGTAC + MMF + corticosteroids
•Dose of TAC: Trough levels (C-0h) of TAC in whole blood should have been maintained between 6-10 ng/mL until Week 52 post-transplant. •Dose of MMF: Doses of 500-1000 mg/12 hrs was maintained until Week 52. •Corticosteroids: During the study, oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted (e.g. in patients with a history of HCV). It was recommended in any case that corticosteroids not be administered beyond Week 24 post-transplant except in cases of hepatopathy of autoimmune origin. At each centre all patients should have followed the same administration protocol for corticosteroids based on history of HCV.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A multicentre, randomized, open-label, controlled, exploratory clinical trial with 12-months (52 weeks) of follow-up.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Screening Visit - Inclusion Criteria 1. Recipients age 18 or over receiving a first liver transplant from a cadaver donor. 2. Patients diagnosed with HCC must meet the Milan radiological criteria at the time of transplant (1 nodule ≤5 cm in diameter, or 2-3 nodules, all \<3 cm in diameter) - at time of patient's inclusion on the waiting list. Anh: done. 3. Patients who have signed the informed consent to participate in the study. 4. Patients who by medical criteria are capable of complying with the study regimen. Screening Visit -
Exclusion criteria
1. Recipients who have received multiple transplants of solid organs or pancreatic islet cells. 2. Patients who have previously received an organ or tissue transplant. 3. Patients with a combined liver-kidney transplant. 4. Recipients of lobes or segments of liver from a live donor. 5. A history of malignancy of any organ system in the previous 3 years according to local protocols (regardless of signs of local recurrence or metastasis), other than non-metastasising basal cell carcinoma or squamous cell carcinoma (epidermoid carcinoma) of the skin, or HCC. 6. Patients with known hypersensitivity to the drugs used in the study or others of their class, or to any of their excipients. 7. Recipients of ABO-incompatible transplants. 8. Patients who test positive for HIV. 9. Recipients of organs from donors who tested positive for the hepatitis B surface antigen or HIV seropositive. 10. Patients with any medical or surgical condition that in the opinion of the investigator may significantly alter the absorption, distribution, metabolism or excretion of the study medication. 11. Women of childbearing potential (i.e. women who are not postmenopausal with amenorrhoea of more than 1 year or surgically sterile) who are planning to become pregnant, are pregnant and/or breastfeeding, or who do not wish to use effective contraception, e.g. hormonal contraceptives (implantation, patches, oral) and double-barrier methods (any double combination of: IUD, male or female condoms with spermicidal gel, diaphragm, contraceptive sponge, cervical cap). 12. Patients who are taking part in another clinical trial. Randomisation Visit - Inclusion Criteria 1. Functioning allograft at the time of randomisation. A functioning allograft is defined as: 1. levels of AST, ALT and total bilirubin ≤ 4 times the upper limit of normal, and 2. levels of alkaline phosphatase and GGT ≤ 5 times the upper limit of normal. 2. Glomerular filtrate ≥30 mL/min/1.73 m2 (calculated using the MDRD-4 equation). Randomisation Visit -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentages of Participants Showing Clinical Benefit by Renal Function Stratification | week 4, week 52. | Clinical benefit is defined as: • an improvement in 1 or 2 ranges of the eGFR, according to MDRD-4 at Week 52 post-transplant in patients with values of 30-\<45 or 45-\<60 mL/min/1.73 m2 in Week 4. or • stabilisation of eGFR in patients with values ≥60 mL/min/1.73 m2 at Week 4 and maintained at Week 52 post-transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Creatinine Clearance - Cockcroft-Gault Formula | Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant | Kidney function was assessed over time by creatine clearance based on the Cockcroft-Gault formula. Estimated creatinine clearance (mL/min) = \[(140 - age) x (weight) x (0.85 if female)\] / (72 x serum creatinine). Units: age (years); weight (kg); serum creatinine (mg/dL). The values of the eGFR according to the creatinine clearance (Cockcroft-Gault formula) for the ITT population were ml/min/1.73 m\^2. |
| Changes in eGFR Based on the MDRD-4 Formula | Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant | Kidney function was assessed over time by changes in eGFR according to the MDRD-4 formula. The MDRD-4 formula (Levey et al., 2000) was used based on serum concentration of creatinine (conventional units): eGFR (mL/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if of African descent). Units: serum creatinine (mg/dL); age (years). |
| eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant | Model for End Stage Liver Disease (MELD) score: ≤14, 15-19, 20-24, 25-29, ≥30. The higher the number indicates the urgency for transplant. |
| Urine Protein/Creatinine Ratio | Screening visit, week 1,4,18,24, and 52 | The urine protein/creatinine ratio was assessed throughout follow-up in both treatment groups. |
| Percentage of Participants With Incidence of Proteinuria | Screening visit, week 1,4,18,24, and 52 | The incidence of proteinuria (≥0.5-0.9 g/day, ≥1.0-2.9 g/day and ≥3.0 g/day) was assessed throughout follow-up in both treatment groups. Proteinuria was defined as protein/creatinine ratio ≥ 0.5. |
| Time to Rejection | Throughout study period, approximately 2 years and 2 months | Time to acute rejection was calculated from the date of transplantation. Acute rejection date was taken from biopsy date, as the date of rejection was not collected. Time to treated BPAR was calculated from the date of transplantation. |
| Severity of Rejection | Throughout study period, approximately 2 years and 2 months | Severity of acute rejection and treated BPAR was graded according to Banff criteria. Grade of acute rejection according to Banff criteria: mild, moderate, severe. |
| Percentages of Participants With HCV-positive and HCV Genotype | approximately 2 years and 2 months | The viral load of HCV-RNA and HCV genotype was assessed in HCV-positive patients. The term genotype was used to describe strains of HCV that vary but were related to the virus. Worldwide, there were 11 primary groups of HCV genotypes designated by the numbers from 1-11, with the most common in our setting being subtypes 1a, 1b, 2 and 3, which were identified in the local laboratory according to their usual testing methods. |
| Concentration of p-P70S6K | weeks 6,8,12,18,24,36,52 at 0 (Cmin), and 1 (C1h) hrs post-dose. | the biomarker of personal response to everolimus, monitoring of the activity of the target, kinase P70 S6, in its phosphorylated form at Thr389. EVR=everolimus Cmin=minimum concentration |
| Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Throughout the study period, approximately 2 years and 2 months | Liver biopsy had to be performed in all cases where acute rejection was suspected. Results of the biopsy were interpreted by the local pathologist (who did not known the treatment given to the patient) according to the Banff classification (1997). Biopsy-proven acute rejection (BPAR) defined as clinical suspicion of acute rejection confirmed in biopsy. Treated BPAR was deemed to be an episode of acute rejection in which the interpretation of the local pathologist showed that it reached any grade of acute rejection under the Banff classification, and for which anti-rejection therapy was administered. Loss of the liver allograft was deemed to have occurred the day that the patient was again included on the waiting list for liver transplant, the day he or she received another allograft or upon the death of the patient. All suspected hepatic allograft rejections were considered acute rejection |
Countries
Spain
Participant flow
Recruitment details
Patients enrolled were 217, patients in the safety population were 215, and patients in the ITT population were 211.
Pre-assignment details
The intention-to-treat population (ITT) that was used for all efficacy analyses included all randomised patients who had received at least one dose of the study medication (safety population) and had at least one assessment subsequent to the randomisation visit for determining the primary efficacy endpoint.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Group Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids | 105 |
| Control Group Treatment with TAC + MMF + corticosteroids | 106 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 6 |
| Overall Study | Death | 6 | 3 |
| Overall Study | Immunosuppressant/prohibited med use | 7 | 10 |
| Overall Study | Protocol Violation | 9 | 11 |
| Overall Study | Transplant rejection/retransplant | 0 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 1 |
Baseline characteristics
| Characteristic | Experimental Group | Control Group | Total |
|---|---|---|---|
| Age, Continuous | 58.43 years STANDARD_DEVIATION 6.37 | 55.84 years STANDARD_DEVIATION 7.45 | 57.13 years STANDARD_DEVIATION 7.04 |
| Sex: Female, Male Female | 14 Participants | 16 Participants | 30 Participants |
| Sex: Female, Male Male | 91 Participants | 90 Participants | 181 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 97 / 106 | 105 / 109 |
| serious Total, serious adverse events | 55 / 106 | 48 / 109 |
Outcome results
Primary
Percentages of Participants Showing Clinical Benefit by Renal Function Stratification
Clinical benefit is defined as: • an improvement in 1 or 2 ranges of the eGFR, according to MDRD-4 at Week 52 post-transplant in patients with values of 30-\<45 or 45-\<60 mL/min/1.73 m2 in Week 4. or • stabilisation of eGFR in patients with values ≥60 mL/min/1.73 m2 at Week 4 and maintained at Week 52 post-transplant.
Time frame: week 4, week 52.
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Group | Percentages of Participants Showing Clinical Benefit by Renal Function Stratification | > = 30 - 45 ml/min/1.73m^2 at Week 52 | 4.76 Percentages of partcipants |
| Experimental Group | Percentages of Participants Showing Clinical Benefit by Renal Function Stratification | > = 45 - <60 ml/min/1.73m^2 at Week 52 | 14.29 Percentages of partcipants |
| Experimental Group | Percentages of Participants Showing Clinical Benefit by Renal Function Stratification | > = 60 ml/min/1.73m^2 at Week 52 | 79.05 Percentages of partcipants |
| Control Group | Percentages of Participants Showing Clinical Benefit by Renal Function Stratification | > = 30 - 45 ml/min/1.73m^2 at Week 52 | 3.77 Percentages of partcipants |
| Control Group | Percentages of Participants Showing Clinical Benefit by Renal Function Stratification | > = 45 - <60 ml/min/1.73m^2 at Week 52 | 16.04 Percentages of partcipants |
| Control Group | Percentages of Participants Showing Clinical Benefit by Renal Function Stratification | > = 60 ml/min/1.73m^2 at Week 52 | 79.25 Percentages of partcipants |
Comparison: Null hypothesis (H0): there were no differences in kidney function between the two groups, in contrast with the alternative hypothesis (H1), in which there were differences:~HO: CBS = CBC versus H1: CBS ≠ CBC, where CBS and CBC were percentages of patients who showed clinical benefit at Week 52 for the study group and control group, respectively.p-value: 0.9423Fisher Exact
Secondary
Changes in Creatinine Clearance - Cockcroft-Gault Formula
Kidney function was assessed over time by creatine clearance based on the Cockcroft-Gault formula. Estimated creatinine clearance (mL/min) = \[(140 - age) x (weight) x (0.85 if female)\] / (72 x serum creatinine). Units: age (years); weight (kg); serum creatinine (mg/dL). The values of the eGFR according to the creatinine clearance (Cockcroft-Gault formula) for the ITT population were ml/min/1.73 m\^2.
Time frame: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 4 | 80.19 ml/min/1.73m^2 | Standard Deviation 28 |
| Experimental Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 24 | 89.57 ml/min/1.73m^2 | Standard Deviation 32.89 |
| Experimental Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 1 | 116.93 ml/min/1.73m^2 | Standard Deviation 44.82 |
| Experimental Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 36 | 94.46 ml/min/1.73m^2 | Standard Deviation 30.26 |
| Experimental Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 12 | 87.76 ml/min/1.73m^2 | Standard Deviation 26.51 |
| Experimental Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 52 | 92.21 ml/min/1.73m^2 | Standard Deviation 29.96 |
| Experimental Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Screening | 104.67 ml/min/1.73m^2 | Standard Deviation 36.4 |
| Control Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 52 | 91.04 ml/min/1.73m^2 | Standard Deviation 37.26 |
| Control Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Screening | 109.69 ml/min/1.73m^2 | Standard Deviation 48.47 |
| Control Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 1 | 118.09 ml/min/1.73m^2 | Standard Deviation 44.82 |
| Control Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 4 | 91.26 ml/min/1.73m^2 | Standard Deviation 37.6 |
| Control Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 12 | 90.14 ml/min/1.73m^2 | Standard Deviation 35.82 |
| Control Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 24 | 87.93 ml/min/1.73m^2 | Standard Deviation 35.92 |
| Control Group | Changes in Creatinine Clearance - Cockcroft-Gault Formula | Week 36 | 90.91 ml/min/1.73m^2 | Standard Deviation 35.96 |
Secondary
Changes in eGFR Based on the MDRD-4 Formula
Kidney function was assessed over time by changes in eGFR according to the MDRD-4 formula. The MDRD-4 formula (Levey et al., 2000) was used based on serum concentration of creatinine (conventional units): eGFR (mL/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if of African descent). Units: serum creatinine (mg/dL); age (years).
Time frame: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Group | Changes in eGFR Based on the MDRD-4 Formula | Week 4 | 82.18 ml/min/1.73m2 | Standard Deviation 28.47 |
| Experimental Group | Changes in eGFR Based on the MDRD-4 Formula | Week 24 | 86.02 ml/min/1.73m2 | Standard Deviation 31.97 |
| Experimental Group | Changes in eGFR Based on the MDRD-4 Formula | Screening | 100.20 ml/min/1.73m2 | Standard Deviation 38.74 |
| Experimental Group | Changes in eGFR Based on the MDRD-4 Formula | Week 36 | 87.68 ml/min/1.73m2 | Standard Deviation 32.49 |
| Experimental Group | Changes in eGFR Based on the MDRD-4 Formula | Week 12 | 85.99 ml/min/1.73m2 | Standard Deviation 25.13 |
| Experimental Group | Changes in eGFR Based on the MDRD-4 Formula | Week 52 | 86.09 ml/min/1.73m2 | Standard Deviation 27.87 |
| Experimental Group | Changes in eGFR Based on the MDRD-4 Formula | Week 1 | 112.86 ml/min/1.73m2 | Standard Deviation 50.06 |
| Control Group | Changes in eGFR Based on the MDRD-4 Formula | Week 52 | 83.23 ml/min/1.73m2 | Standard Deviation 25.24 |
| Control Group | Changes in eGFR Based on the MDRD-4 Formula | Week 1 | 112.15 ml/min/1.73m2 | Standard Deviation 48.16 |
| Control Group | Changes in eGFR Based on the MDRD-4 Formula | Screening | 99.42 ml/min/1.73m2 | Standard Deviation 43.09 |
| Control Group | Changes in eGFR Based on the MDRD-4 Formula | Week 4 | 88.39 ml/min/1.73m2 | Standard Deviation 34.32 |
| Control Group | Changes in eGFR Based on the MDRD-4 Formula | Week 12 | 83.57 ml/min/1.73m2 | Standard Deviation 28.19 |
| Control Group | Changes in eGFR Based on the MDRD-4 Formula | Week 24 | 82.00 ml/min/1.73m2 | Standard Deviation 26.93 |
| Control Group | Changes in eGFR Based on the MDRD-4 Formula | Week 36 | 83.04 ml/min/1.73m2 | Standard Deviation 25.56 |
Secondary
Concentration of p-P70S6K
the biomarker of personal response to everolimus, monitoring of the activity of the target, kinase P70 S6, in its phosphorylated form at Thr389. EVR=everolimus Cmin=minimum concentration
Time frame: weeks 6,8,12,18,24,36,52 at 0 (Cmin), and 1 (C1h) hrs post-dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Group | Concentration of p-P70S6K | Cmin EVR week 12 | 4.4 ng/ml | Standard Deviation 1.8 |
| Experimental Group | Concentration of p-P70S6K | C1h EVR week 12 | 16 ng/ml | Standard Deviation 9.5 |
| Experimental Group | Concentration of p-P70S6K | Cmin EVR week 6 | 3.8 ng/ml | Standard Deviation 1.7 |
| Experimental Group | Concentration of p-P70S6K | C1h EVR week 6 | 6.8 ng/ml | Standard Deviation 6.3 |
| Experimental Group | Concentration of p-P70S6K | Cmin EVR week 8 | 4.7 ng/ml | Standard Deviation 1.6 |
| Experimental Group | Concentration of p-P70S6K | C1h EVR week 8 | 9.5 ng/ml | Standard Deviation 4.9 |
| Experimental Group | Concentration of p-P70S6K | Cmin EVR week 18 | 6.8 ng/ml | Standard Deviation 2.7 |
| Experimental Group | Concentration of p-P70S6K | C1h EVR week 18 | 14.6 ng/ml | Standard Deviation 6.7 |
| Experimental Group | Concentration of p-P70S6K | Cmin EVR week 24 | 5.3 ng/ml | Standard Deviation 2.13 |
| Experimental Group | Concentration of p-P70S6K | C1h EVR week 24 | 18 ng/ml | Standard Deviation 7.2 |
| Experimental Group | Concentration of p-P70S6K | Cmin EVR week 36 | 5.1 ng/ml | Standard Deviation 1.35 |
| Experimental Group | Concentration of p-P70S6K | C1h EVR week 36 | 12.7 ng/ml | Standard Deviation 4.2 |
| Experimental Group | Concentration of p-P70S6K | Cmin EVR week 52 | 5.35 ng/ml | Standard Deviation 0.97 |
| Experimental Group | Concentration of p-P70S6K | C1h EVR week 52 | 16.1 ng/ml | Standard Deviation 7.6 |
Secondary
eGFR Values(MDRD-4 Formula) According to the MELD Score
Model for End Stage Liver Disease (MELD) score: ≤14, 15-19, 20-24, 25-29, ≥30. The higher the number indicates the urgency for transplant.
Time frame: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant
Population: ITT population (patients with MDRD-4 values).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 81.96 ml/min/1.73m^2 |
| Experimental Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 85.81 ml/min/1.73m^2 |
| Experimental Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 96.63 ml/min/1.73m^2 |
| Experimental Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 114.00 ml/min/1.73m^2 |
| Experimental Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 80.76 ml/min/1.73m^2 |
| Experimental Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 86.14 ml/min/1.73m^2 |
| Experimental Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 81.37 ml/min/1.73m^2 |
| Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 81.41 ml/min/1.73m^2 |
| Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 93.31 ml/min/1.73m^2 |
| Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 88.76 ml/min/1.73m^2 |
| Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 88.94 ml/min/1.73m^2 |
| Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 92.44 ml/min/1.73m^2 |
| Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 90.29 ml/min/1.73m^2 |
| Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 85.19 ml/min/1.73m^2 |
| 20 to 24 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 78.88 ml/min/1.73m^2 |
| 20 to 24 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 88.89 ml/min/1.73m^2 |
| 20 to 24 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 70.57 ml/min/1.73m^2 |
| 20 to 24 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 75.62 ml/min/1.73m^2 |
| 20 to 24 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 83.91 ml/min/1.73m^2 |
| 20 to 24 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 83.45 ml/min/1.73m^2 |
| 20 to 24 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 71.60 ml/min/1.73m^2 |
| 25 to 29 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 75.94 ml/min/1.73m^2 |
| 25 to 29 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 137.61 ml/min/1.73m^2 |
| 25 to 29 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 104.45 ml/min/1.73m^2 |
| 25 to 29 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 83.09 ml/min/1.73m^2 |
| 25 to 29 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 84.86 ml/min/1.73m^2 |
| 25 to 29 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 94.82 ml/min/1.73m^2 |
| 25 to 29 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 83.94 ml/min/1.73m^2 |
| > = 30 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 56.67 ml/min/1.73m^2 |
| > = 30 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 38.35 ml/min/1.73m^2 |
| > = 30 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 53.93 ml/min/1.73m^2 |
| > = 30 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 82.04 ml/min/1.73m^2 |
| > = 30 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 58.07 ml/min/1.73m^2 |
| > = 30 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 69.43 ml/min/1.73m^2 |
| > = 30 | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 60.37 ml/min/1.73m^2 |
| <= 14 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 83.63 ml/min/1.73m^2 |
| <= 14 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 102.27 ml/min/1.73m^2 |
| <= 14 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 108.64 ml/min/1.73m^2 |
| <= 14 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 89.44 ml/min/1.73m^2 |
| <= 14 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 80.01 ml/min/1.73m^2 |
| <= 14 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 86.72 ml/min/1.73m^2 |
| <= 14 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 80.92 ml/min/1.73m^2 |
| 15 to 19 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 67.00 ml/min/1.73m^2 |
| 15 to 19 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 70.27 ml/min/1.73m^2 |
| 15 to 19 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 72.76 ml/min/1.73m^2 |
| 15 to 19 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 67.90 ml/min/1.73m^2 |
| 15 to 19 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 92.98 ml/min/1.73m^2 |
| 15 to 19 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 93.85 ml/min/1.73m^2 |
| 15 to 19 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 70.32 ml/min/1.73m^2 |
| 20 to 24 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 91.45 ml/min/1.73m^2 |
| 20 to 24 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 90.66 ml/min/1.73m^2 |
| 20 to 24 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 82.64 ml/min/1.73m^2 |
| 20 to 24 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 87.22 ml/min/1.73m^2 |
| 20 to 24 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 86.17 ml/min/1.73m^2 |
| 20 to 24 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 89.67 ml/min/1.73m^2 |
| 20 to 24 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 119.19 ml/min/1.73m^2 |
| 25 to 29 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 99.50 ml/min/1.73m^2 |
| 25 to 29 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 74.82 ml/min/1.73m^2 |
| 25 to 29 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 85.23 ml/min/1.73m^2 |
| 25 to 29 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 156.41 ml/min/1.73m^2 |
| 25 to 29 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 65.01 ml/min/1.73m^2 |
| 25 to 29 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 68.32 ml/min/1.73m^2 |
| 25 to 29 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 88.34 ml/min/1.73m^2 |
| > = 30 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 36 | 65.58 ml/min/1.73m^2 |
| > = 30 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 52 | 63.26 ml/min/1.73m^2 |
| > = 30 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 1 | 86.45 ml/min/1.73m^2 |
| > = 30 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 24 | 62.74 ml/min/1.73m^2 |
| > = 30 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 12 | 81.92 ml/min/1.73m^2 |
| > = 30 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Screening | 53.73 ml/min/1.73m^2 |
| > = 30 Control Group | eGFR Values(MDRD-4 Formula) According to the MELD Score | Week 4 | 78.57 ml/min/1.73m^2 |
Secondary
Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR
Liver biopsy had to be performed in all cases where acute rejection was suspected. Results of the biopsy were interpreted by the local pathologist (who did not known the treatment given to the patient) according to the Banff classification (1997). Biopsy-proven acute rejection (BPAR) defined as clinical suspicion of acute rejection confirmed in biopsy. Treated BPAR was deemed to be an episode of acute rejection in which the interpretation of the local pathologist showed that it reached any grade of acute rejection under the Banff classification, and for which anti-rejection therapy was administered. Loss of the liver allograft was deemed to have occurred the day that the patient was again included on the waiting list for liver transplant, the day he or she received another allograft or upon the death of the patient. All suspected hepatic allograft rejections were considered acute rejection
Time frame: Throughout the study period, approximately 2 years and 2 months
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Group | Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Patients with suspected acute rejection | 17.14 Percentages of participants |
| Experimental Group | Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Patients with BPAR | 5.71 Percentages of participants |
| Experimental Group | Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Patients with treated BPAR | 4.76 Percentages of participants |
| Control Group | Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Patients with suspected acute rejection | 15.09 Percentages of participants |
| Control Group | Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Patients with BPAR | 3.77 Percentages of participants |
| Control Group | Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR | Patients with treated BPAR | 1.89 Percentages of participants |
Secondary
Percentage of Participants With Incidence of Proteinuria
The incidence of proteinuria (≥0.5-0.9 g/day, ≥1.0-2.9 g/day and ≥3.0 g/day) was assessed throughout follow-up in both treatment groups. Proteinuria was defined as protein/creatinine ratio ≥ 0.5.
Time frame: Screening visit, week 1,4,18,24, and 52
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 1 | 6.45 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 18 | 0.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at screening | 2.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 18 | 1.39 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 1 | 0.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 18 | 1.39 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at screening | 2.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 24 | 7.58 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 4 | 5.21 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 24 | 0.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 1 | 3.23 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 24 | 1.52 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 4 | 0.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 52 | 6.67 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at screening | 0.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 52 | 3.33 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 4 | 0.00 Percentages of participants |
| Experimental Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 52 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 4 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at screening | 3.77 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at screening | 1.89 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at screening | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 1 | 18.31 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 1 | 5.63 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 1 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 4 | 1.05 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 4 | 1.05 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 52 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 18 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 18 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 18 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 24 | 1.52 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 24 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 3.0 g/day at Week 24 | 0.00 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 0.5-1.0 g/day at Week 52 | 1.89 Percentages of participants |
| Control Group | Percentage of Participants With Incidence of Proteinuria | ≥ 1.0-3.0 g/day at Week 52 | 1.89 Percentages of participants |
Secondary
Percentages of Participants With HCV-positive and HCV Genotype
The viral load of HCV-RNA and HCV genotype was assessed in HCV-positive patients. The term genotype was used to describe strains of HCV that vary but were related to the virus. Worldwide, there were 11 primary groups of HCV genotypes designated by the numbers from 1-11, with the most common in our setting being subtypes 1a, 1b, 2 and 3, which were identified in the local laboratory according to their usual testing methods.
Time frame: approximately 2 years and 2 months
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Group | Percentages of Participants With HCV-positive and HCV Genotype | Hepatitis C virus (HVC) positive | 33.33 Percentages of participants |
| Experimental Group | Percentages of Participants With HCV-positive and HCV Genotype | HCV genotype 04 | 2.86 Percentages of participants |
| Experimental Group | Percentages of Participants With HCV-positive and HCV Genotype | HCV genotype 03 | 17.14 Percentages of participants |
| Experimental Group | Percentages of Participants With HCV-positive and HCV Genotype | HCV genotype 01 | 80.00 Percentages of participants |
| Control Group | Percentages of Participants With HCV-positive and HCV Genotype | HCV genotype 01 | 76.92 Percentages of participants |
| Control Group | Percentages of Participants With HCV-positive and HCV Genotype | non-responders | 10.26 Percentages of participants |
| Control Group | Percentages of Participants With HCV-positive and HCV Genotype | Hepatitis C virus (HVC) positive | 36.79 Percentages of participants |
| Control Group | Percentages of Participants With HCV-positive and HCV Genotype | HCV genotype 03 | 10.26 Percentages of participants |
| Control Group | Percentages of Participants With HCV-positive and HCV Genotype | HCV genotype 04 | 2.56 Percentages of participants |
Secondary
Severity of Rejection
Severity of acute rejection and treated BPAR was graded according to Banff criteria. Grade of acute rejection according to Banff criteria: mild, moderate, severe.
Time frame: Throughout study period, approximately 2 years and 2 months
Population: ITT
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Experimental Group | Severity of Rejection | Severity of acute rejection: Severe(Grade III) | 0.00 Percentages of participants | — |
| Experimental Group | Severity of Rejection | Severity of acute rejection: Mild (Grade I) | 13.64 Percentages of participants | 3.15 |
| Experimental Group | Severity of Rejection | Severity of acute rejection: Moderate(Grade II) | 13.64 Percentages of participants | 1.5 |
| Experimental Group | Severity of Rejection | Severity of treated BPAR: Mild (Grade I) | 33.33 Percentages of participants | — |
| Experimental Group | Severity of Rejection | Severity of treated BPAR: Moderate(Grade II) | 50.00 Percentages of participants | — |
| Experimental Group | Severity of Rejection | Severity of treated BPAR: Severe(Grade III) | 0.00 Percentages of participants | — |
| Control Group | Severity of Rejection | Severity of treated BPAR: Moderate(Grade II) | 50.00 Percentages of participants | — |
| Control Group | Severity of Rejection | Severity of treated BPAR: Mild (Grade I) | 0.00 Percentages of participants | — |
| Control Group | Severity of Rejection | Severity of acute rejection: Mild (Grade I) | 11.11 Percentages of participants | 2.89 |
| Control Group | Severity of Rejection | Severity of treated BPAR: Severe(Grade III) | 50.00 Percentages of participants | — |
| Control Group | Severity of Rejection | Severity of acute rejection: Moderate(Grade II) | 5.56 Percentages of participants | 5.25 |
| Control Group | Severity of Rejection | Severity of acute rejection: Severe(Grade III) | 5.56 Percentages of participants | — |
Secondary
Time to Rejection
Time to acute rejection was calculated from the date of transplantation. Acute rejection date was taken from biopsy date, as the date of rejection was not collected. Time to treated BPAR was calculated from the date of transplantation.
Time frame: Throughout study period, approximately 2 years and 2 months
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Group | Time to Rejection | Time to acute rejection | 3.74 months | Standard Deviation 3.15 |
| Experimental Group | Time to Rejection | Time to treated BPAR | 2.65 months | Standard Deviation 1.5 |
| Control Group | Time to Rejection | Time to acute rejection | 2.91 months | Standard Deviation 2.89 |
| Control Group | Time to Rejection | Time to treated BPAR | 3.85 months | Standard Deviation 5.25 |
Secondary
Urine Protein/Creatinine Ratio
The urine protein/creatinine ratio was assessed throughout follow-up in both treatment groups.
Time frame: Screening visit, week 1,4,18,24, and 52
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Group | Urine Protein/Creatinine Ratio | Screening | 199.89 mg/g | Standard Deviation 582.03 |
| Experimental Group | Urine Protein/Creatinine Ratio | Week 1 | 252.48 mg/g | Standard Deviation 308.22 |
| Experimental Group | Urine Protein/Creatinine Ratio | Week 4 | 134.77 mg/g | Standard Deviation 175.05 |
| Experimental Group | Urine Protein/Creatinine Ratio | Week 18 | 204.26 mg/g | Standard Deviation 688.05 |
| Experimental Group | Urine Protein/Creatinine Ratio | Week 24 | 200.17 mg/g | Standard Deviation 466.55 |
| Experimental Group | Urine Protein/Creatinine Ratio | Week 52 | 219.41 mg/g | Standard Deviation 406.52 |
| Control Group | Urine Protein/Creatinine Ratio | Week 24 | 120.52 mg/g | Standard Deviation 108.04 |
| Control Group | Urine Protein/Creatinine Ratio | Screening | 131.56 mg/g | Standard Deviation 178.95 |
| Control Group | Urine Protein/Creatinine Ratio | Week 18 | 105.02 mg/g | Standard Deviation 79.61 |
| Control Group | Urine Protein/Creatinine Ratio | Week 1 | 349.46 mg/g | Standard Deviation 396.44 |
| Control Group | Urine Protein/Creatinine Ratio | Week 52 | 143.05 mg/g | Standard Deviation 220.72 |
| Control Group | Urine Protein/Creatinine Ratio | Week 4 | 141.71 mg/g | Standard Deviation 187.11 |